Carboxylated monosubstituted



Patented Aug. 3, 1945;

CARBOXYLATED MONOSUBSTITUTED BARBITURIC ACID Wilhelm Wenner, Montclair', N. J., assignor'to Hoffmann-La Roche Inc., Nutley, N. J a corporation of New Jersey No Drawing. Application J anuary'lS, 1946,

Serial No. 642,110

18 Claims.

My invention relates to carboxy-lated monosubstituted barbituric acids useful as interme diates for medicinal agents and-to the process of manufacture of these novel compounds.

My new compounds may be in general represented as:

in which n is zero oran integer, and in which A, B, and X represent hydrogen or alkyl.

For the purpose of simplifying the understanding of the 7 subject matter, the designation Barb will be employed hereinafter to represent the monovalent barbituric acid residue:

(111) EN-C 0% {Ha HN-CO I have found that these new derivatives can be obtained in satisfactory yields by the catalytic hydrogenation of barbituric acid in the presence of at least one stoichiometric molecular equivalent of a keto-acid ester of the general formulae:

allkyl CO(CAB)..COO alkyl and ringalkylene- 0c {-000 alkyl The general scheme of the new reaction typified by the following equation, in which A and B are hydrogen is that in which ethyl acetoacetate and barbituric acid are hydrogenated:

(I V) CE:

As a result of this reaction, a final product is obtained (IV) which is 5-(p-carbethoxy-amethyl-ethyD-barbituric acid. This ester is easily soluble in ethanol or methanol. It can be recrystallized from water. Crystallization proceeds slowly. The pure compound has almelting point of 163-164. The ester can be saponified by alkalies, yielding the corresponding salt,

which upon acidification, produces theiree acid represented by the formula:

( ([7113 v Bar'b-HC-OH2COOH The reactionwith methyl acetoacetate yields the corresponding methyl ester of melting point of 164-165" which closely resembles the ethyl ester in its chemical behavior and has nearly the same melting point. Upon saponification; it gives the same acid (V) as is obtained from the ethyl ester (IV). The methyl ester is less soluble, however, than the ethyl ester.

I have found that my novel compounds can be prepared from a variety of keto-acid esters.

Examples of suitable esters which may be employed will'be shown hereinafter. It will be apparent from the general Formulae I and, II,

given above, that the keto-acid esters may be substituted, that is A and/or B may be alkyl. For example, a mono-substituted ester may be used, such as, the compound represented by the formula; V

(VI) CH3 C2115 A dialkyl substituted ester may also be employed, as for example ethyl dimethyl acetoacetate.

An example of a starting ester in which n is zero is ethyl pyruvate. Y

Cycloalkyl keto-esters, such as ethyl-cyclopentanon-2-carboxylate, of Formula VII, may be employed:

Similarly, the cyclohexanon ester of Formula VIII may be used: v

(VIII), 00002115 912F031 /CH2 7 v our-cm I Upon hydrogenation with barbituric acid, these two cyclic esters yield, respectively, 5-(o-carbethoxy-cyclopentyl) -barbituric acid (IX) and 5-(o-carbethoxy cyclohexyl) barbituric acid (X):

GENERAL PROCEDURE In general, the reaction may be carried out as follows:

turic. acid. h sa ular .ke epid es er. and a sol vent such as an alcohol, for example methanol or ethanol, are placed in a hydrogenation autoclave. A noble metal catalyst, such as palladium charcoal is also employed. The palladium content of the charcoal can varywithin Wide limits, 3%, in most instances, being as suitable as 20%. It may be desirable to. promote the reaction by the use of ammonium acetate. The pressure may be as low as 100 lbs, but I prefer to use at least 500 lbs. The temperature does not appear to be critical as long as it does not produce decomposition. The reaction preterably carried out with a slight excess of ketoacid este amou t o solvent an. h relatively small; for ample o the or er or shout 30-80 cc. of alcohol for10-20 g. of barbituric acid.

The isolation of the product depends upon the nature thereof. Where the new compound is crystallized. it is best fi ter d t g h r with t e. ca alrst f l owed by remera oi the catal st in a rec ystal ization proce s The mo her; lia e ma conta n. a d i na amo n s at th p o u t w ch he e orera by. dis latien' the sol ent In th se a e Whe e h roduct is no teens cr s l zed aiter her et ea he. sqlm tions are ed. it m the ca al st the fil r tes are exasperated. he es d ry a liz in alqstcases the ro uc btained first stenc it s lidifie u on. the a di i n o water! and r crrs a a iqo from ater yi lds'a cur co ou dhen w c m ounds ar rat er soluble low lig r tic alcohol an s so n water- The! ca 9 the os oar-t. be r c tal ized rom bo l ng water. M st of. the new p oducts. D$$S the characteristic odor of barbituric acids, al: though not very distinctly. The compounds are practically insoluble in benzene, or in petroleum ether. The compounds are soluble in alkali. The 1 19 adds. r e lk i s l whic are h h y sol ble n wate 1 The following examples are presented to. illus= hate embod m nt o my inreetica ho ever, it will be understood that, thee garnples are intended to be ty c l of. the bread reaction an ha th Particu a r trea s emrlwesl. as well as the conditions under which the. reactions are carried out, are not to be taken as restrictive in nature. The products may be prepared and used in either a pure or an impure state.

EXAMPLE 1:

5- (p-carbomethoan -a-methyZ-ethyl) barbituric acid 1 200 g. of technical barbituric acid, 220 g. of methyl acetoacetate, 10 g. of palladium charcoal, containing 1 g. of palladium, and 400 cc. of methanol are hydrogenated at 8 6.90 and 600- lbs. pressure for 20 hours. Most of the reaction product crystallizes. 2500 cc. of methanol are added and the mixture refluxed. The crystals dissolve and the hot solution is filtered from the catalyst. The filtrate is cooled for several hours to The main amount of the compound crystallizes and is filtered. The mother liquor is concentrated to a small volume giving a second crop. Reor-ysr, tallization irom methanol giyes the pure compound of M. P. res-16s.

EXAMPLE 2 (fi-carbethoaryq emcthyleethyl) -.barbitur2'c acid 200 .g. fbarbituric acid, 215 g. of ethyl acetoacetate, 10 g. of palladium charcoal, containing 1 a ct cal si ula an 9 cc. Qf. arie l cr v are ydrogenated at -100" and: 700 lbs. pressure for 18 hours. Part of the reaction product is crystallized. It is dissolved by addition of methanol and heating. The hot solution is filtered from the catalyst and cooled in a refrigerator. Crystals separate and are filtered. The mother liquor isiconcentratedr 0n cooling, a second crop is obtained. The crude product melts at -159. Recrystallization from methanol gives the pure e ter 5 16 .7

EXAMPLE 3 5 (,8-carbethoxy-a-metisyl-butyl -barbituric acid 5: s,- q: Pastime-. a d. .6 ger ethyl hy eete ate 2 salla i-um Q ZQ EQ QJ 9.313%? i l 8:- animal acetate 1 are hrd ceeatee at mixture is filtered and the filtrate cvapor ted to dryness. The oily residue is treated with water. It crystallizes soon and is filtered. Recrystalliza: tion from about 300 cc. of water glues the pure ester of M. P. 159-161.

EXAMPLE 4 5 (c-carbethomy-a,p-dimgtl yl-pro oyl)eharbituric acid 10 g. of barbituric acid, 12 g. of ethyl dimethylacctoacetate, 0.5 g, of palladium charcoal cont iem 0-0 a 0i a l dium! of amaca um acetate, and 30 1 bi ba a a h ro e a d at .HQ lQ-Q ca 69 lbser r sure qr .24 hou eaqti mi r fi e d. th fil ate d stil ed to. r ess nd the il? re ue. trea d wit watert s ew-l ll cr s als ar filtered and recrystallized from water and alcohol. The pure compound has P. 204-205".

EXAMPLE 5 5- -carbethoxy-a-methyl-n-propyl) -barbituric acid 70 g. of barbituric acid, 84; g. oi; ethyl levulinate, 5 i -P la iu ha coa sw i 9 palladium, and 200 cc. ofrnethanol are hydro: genated at 90-100- and 600 lbs. pressure for 20 hours. The solution is filtered. The filtrate is distilled to a small volume and cooled. The crude ester separates slowly. The mother liquor is evaporated nearly to dryness. On standing for several days, it crystallizes to a solid cake. Etc; crystallization from water gives 46 g. of pure ester. M. P. 102-105".

EXAMPLE '7 5- (o-conlgethozry-cyclopentyl) -bqrbjturic acid 3 sbsrb ri a d 6 of Tb 9? leeee qa f -mmsieium a etat is a n l ediu a see -he onta n n a of palw la a d 3. f met ea a dro ena es and. -9 1er re re 5' hoursqi t e prete rrstall ssman r-attest. 6

450 cc. of methanol is added and the mixture refluxed. The hot solution is filtered and cooled. The ester crystallizes slowly. It is filtered. The mother liquor is evaporated to a small volume, yielding a second crop. Recrystallization from methanol gives the pure ester of M. P. 208-210.

EXAMPLE 8 5- (o-carbethoxy-cyclohemyl) -barbituric acid 13 g. of barbituric acid, 18 g. of Z-carbethoxycyclohexanon, 1 g. of palladium charcoal containing 0.1 g. of palladium, and 40 cc. of methanol are hydrogenated at 90 and 600 lbs. pressure for 8 hours. The mixture is filtered and the filtrate evaporated to dryness. The residue is treated with water, filtered and recrystallized from water. The pure ester has M. P. 158-160".

EXAMPLE 9 5- (p-carboxy-a-methyl-ethyl) -barbitun'c acid 24 g. of the ester formed in Example 2 are dissolved in 100 cc. of sodium hydroxide and warmed to 60 for minutes. After cooling, 50 cc. of concentrated hydrochloric acid are added slowly and the solution cooled in the refrigerator overnight. The acid separates as a fine crystalline powder. It is filtered and recrystallized from water. M. P. 196197.

By the general method corresponding to that of Example 9, 5-(o-carboxy-cyclohexyl) -barbituric acid, M. P. 162, was obtained from 5-(o-carbethoxy-cyclohexyl)-barbituric acid; and 5-(ycarboxy-e-methyl-propyl)-barbituric acid, M. P. 195, was obtained from 5 (7 carbethoxy a methyl-propyl) -barbituric acid.

It will be understood that barbituric acid in all its tautomeric forms will be embraced wherever the term barbituric acid, its pictorial representatives, or its nuclear abbreviation "Barb is employed throughout the specification and claims.

I claim:

1. Compounds of the group consisting of those corresponding to the general formulae:

HN-CO alkyl 0d JJH-H( 3(oAB),.-oo0x and HN-O O cycloaliphatic- 1 0 cHH :J {-ooox HN-GO' in which A, B, and X are members selected from the group consisting of hydrogen and alkyl and in which n is a member of the group consisting of zero and an integer.

2. Compounds corresponding to those of the general formula:

HN-OO alkyl 0 oH-Ho oAB)..-ooox HN- o in which A, B, and X are members selected from the group consisting of hydrogen and alkyl and in which n is a member of the group consisting of zero and an integer.

3. Compounds corresponding to those of the general formula:

EN-C O I- cycloaliphatict t a o IH-H| -ooox HN-O o l I in which X is a member selected from the group consisting of hydrogen and alkyl.

4. Compounds of claim 1 in which X is alkyl.

5. Compounds of claim 2 in which X is alkyl.

6. Compounds of claim 3 in which X is alkyl.

'7. 5 (/3 carbethoxy-u-methyl-ethyl)-barbituric acid.

8. 5 ('y-carbethoxy-a-methyl-propyl) barbituric acid.

9. 5 (o carbethoxy-cyclohexyl) -barbituric acid.

10. The process of making 5-mono-substitutedbarbituric acid, which comprises hydrogenating barbituric acid in the presence of at least one molecular equivalent of a keto-acid ester selected from the group consisting of those corresponding to the general formulae:

alkyl JO(CAB),.O O 0 alkyl and -cycloaliphatio 1 -o o 0 alkyl in which A and B are members selected from the group consisting of hydrogen and alkyl, and n is a member of the group consisting of zero and an integer so as to produce the said 5-monosubstituted barbituric acid.

11. The process of claim 10 in which a ketoacid ester corresponding to the following general formula is employed:

in which A and B are members selected from the group consisting of hydrogen and alkyl, and n is a member of the group consisting of zero and an integer.

12. The process of claim 10 in which a ketoacid ester corresponding to the following formula is employed:

-cycloaliphatico {-000 alkyl 13. The process of claim 10 in which the ketoacid ester is ethyl acetoacetate.

14. The process of claim 10 in which the ketoacid ester is ethyl levulinate.

15. The process of claim 10 in which the ketoacid ester is 2-carbethoxy-cyclohexanon.

16. The process of claim 10 in which the hydrogenation is carried out in the presence of a catalyst.

17. The process of claim 10 in which the hydrogenation is carried out in the presence of a noble-metal catalyst.

18. The process of claim 10 in which the hydrogenation is carried out in the presence of palladium charcoal.

WILHEIM WENNER.

REFERENCES CITED The following references are record in the file of this patent:

American Chemical Journal, vol. 49, pp. and 192.

Leibigs Annalen 335, pp. 334-367 (1904). 

